Livedoid vasculopathy: A multidisciplinary clinical approach to diagnosis and management.

Текст сохранён. Часть иллюстраций пока доступна только в первоисточнике; загрузка будет проверена повторно.

What is known about this subject regarding women and their families? • Livedoid vasculopathy (LV) affects women more often than men (female:male ratio ∼3:2). This increased risk of LV in women might be related to sex-specific physiological conditions, such as pregnancy, or a higher incidence of LV-associated conditions, such as connective tissue diseases, hypercoagulable states, and venous stasis in women. Furthermore, various inherited coagulation abnormalities have been identified in patients with LV; thus, possible underlying genetic abnormalities must be uncovered to protect other family members. • Disfiguring complications, especially painful ulcers and scarring, could have detrimental effects on social and personal relationships and substantially deteriorate patients’ quality of life. • The literature published to date is scarce and/or absent regarding specific considerations for women, the differences between sexes in terms of genetic susceptibility, therapeutic choices, and outcomes, as well as quality of life and long-term results. What is new from this article as messages for women and their families? • Significantly few high-quality studies have addressed problems regarding livedoid vasculopathy (LV) and therapeutic choices. • Reviews and consensus papers are of utmost importance because they show the scientific gap regarding the disease and treatment for specific groups. The current review reveals an urgent need to study and identify specific approaches regarding epidemiologic differences between the sexes, underlying conditions, quality of life, management, and long-term results for LV. • Recently, an association of LV with certain genetic variants, especially PAI-1-675 4G/5G, is highlighted. • Anticoagulants are the most reported monotherapy recently and can be selected in patients with thrombophilia and/or without significant improvement after antiplatelet treatment. Rivaroxaban is preferred due to its advantage of oral administration and the unnecessity of international normalized ratio follow-up, which increases patient compliance.

Introduction

Livedoid vasculopathy (LV) is a rare, chronic, and recurrent thrombo-occlusive disease of the veins supplying the upper parts of the skin ( Alavi et al., 2013 ). It has had several names due to its complicated nature, including livedo vasculitis, segmental hyalinizing vasculitis, livedo reticularis with summer ulceration, Milian white atrophy, atrophie blanche en plaque, and painful purpuric ulcers with a reticular pattern of lower extremities (or PURPLE) since its first description by Milian (1929) . However, Bard and Winkelmann (1967) first used the term livedoid vasculopathy in 1967. The primary pathology is hypercoagulability, although inflammation plays a secondary role. Thus, LV is different from inflammatory vasculitis and classified as a coagulating disorder, a vasculopathy, which occurs when a thrombus forms in the arterial lumen and compromises blood flow. LV shows a chronic course with periodic and recurrent exacerbations, often affecting the legs bilaterally ( Criado et al., 2011 ). Definite diagnosis of LV is based on clinical manifestations and histopathological findings. LV substantially affects patients' quality of life because of its recurrent clinical course, pain, and scarring.

Early diagnosis and treatment before ulcer development can reduce pain and prevent the development of scarring, disfigurement, and other complications. Therefore, a multidisciplinary team approach involving professionals from pathology, rheumatology, hematology, radiology, cardiac surgery, infectious disease, and oncology is imperative for accurate diagnosis, identification of underlying conditions, and optimal treatment.

The literature published to date is scarce and/or absent regarding specific considerations for women, differences between the sexes in terms of genetic susceptibility, therapeutic choices and outcomes, quality of life, and long-term results. This review provides a detailed overview of epidemiology, pathogenesis, clinical features, and treatment of the disease. However, in this comprehensive review, we have mainly focused on key issues regarding diagnosis/differential diagnosis and clinical management of LV with a holistic approach. In addition, we tried to identify the research gap in the literature to form the basis for further research.

Epidemiology

LV often occurs in young to middle-aged adults and affects woman more often (female:male ratio ∼2:3; Criado et al., 2011 ; Gonzalez-Santiago and Davis, 2012 ; Micieli and Alavi, 2018 ; Winkelmann et al., 1974 ). This increased risk for LV in women might be related to sex-specific physiological conditions, such as pregnancy ( Sankar and Hinshaw, 2009 ) or a higher incidence of LV-associated conditions, such as connective tissue diseases, hypercoagulable states, and venous stasis, in women. The incidence of LV is estimated at 1:100,000 ( Alavi et al., 2013 ; Criado et al., 2011 ). Epidemiologic data also suggest that there is a 5-year delay in the adequate diagnosis and management of this condition ( Freitas et al., 2018 ). Possible reasons for the delay in diagnosis can be that patients do not consult dermatologists in the early stages of cutaneous findings, cutaneous lesions usually initially cause minimal subjective complaints, and the current clinical picture can be confused with cutaneous findings that may accompany venous insufficiency, especially venous ulcers.

Pathogenesis

LV pathogenesis is not yet fully known. Initially, it was considered to be vasculitis. However, recent consensus suggests that changes in the local or systemic control mechanism of coagulation lead to the formation of fibrin thrombi in superficial dermal vessels. The thrombotic effect results from defects in the endothelial cell plasminogen activation, platelet dysfunction, or enhanced fibrin formation ( Vasudevan et al., 2016 ). This dermal-vessel thrombosis leads to superficial tissue ischemia and necrosis, causing ulceration and debilitating pain ( Amato et al., 2006 ; Hairston et al., 2006 ; Vasudevan et al., 2016 ). Low tissue perfusion further leads to poor wound healing and ineffective killing of microorganisms by leucocytes, enhancing the chance of infection ( Vasudevan et al., 2016 ).

Patients with LV also show decreased flow-mediated vasodilation of the brachial artery, signifying endothelial dysfunction and decreased production or activity of nitrous oxide in endothelial cells, supporting the contribution of endothelial damage to LV ( Alavi et al., 2013 ; Yang et al., 2012 ). Therapeutic response to immunosuppressive and immunomodulatory agents and association with other autoimmune disorders also supports the involvement of autoimmunity in etiopathogenesis. Increased perfusion pressure at the ankles also appears to play an important role ( Vasudevan et al., 2016 ). LV can be categorized as primary (idiopathic) or secondary LV, in which a known underlying condition causes the disease ( Alavi et al., 2013 ).

Although some mechanisms in the etiopathogenesis of LV and COVID-19–associated livedoid lesions have similar features, COVID-19 infection-causing LV has not yet been reported ( Llamas-Velasco et al., 2020 ). Recently, COVID-19-induced recurrence of LV in a 34-year-old female patient with no other comorbidities or coagulative disorders has been reported ( Valentim et al., 2021 ).

Histopathology

A clinical presentation of LV is characteristic; however, biopsy is necessary to exclude other entities in the differential diagnosis and confirm LV diagnosis. Characteristic histological findings include thickening (endothelial proliferation) or hyalinized degeneration of the subintimal layer of superficial dermal vessels along with intraluminal fibrin deposits, intraluminal thrombosis, red blood cell extravasation, and scarce perivascular lymphocytic infiltration ( Bard and Winkelmann, 1967 ; Haunson et al., 2012 ). No signs of true vasculitis in the form of leukocyte infiltrate on the vessel walls are seen ( Criado et al., 2011 ; Hesse and Kutzner, 2008 ). Thus, the histopathological findings allow clinicians to better classify LV as vasculopathy instead of immune-complex-mediated necrotizing vasculitis ( Fig. 1 ; Criado et al., 2011 ; McCalmont et al., 1992 ). Fig. 1 Diagnostic approach to livedoid vasculopathy. Fig 1

Histopathological findings depend on the age of the lesion, and due to the focal and segmental involvement pattern of LV, classic histopathological findings may not be observed with the biopsy. Thus, attention should be given to the appropriate biopsy method ( Alavi et al., 2013 ). Early lesions show intraluminal hyaline thrombi in small vessels in the mid- and papillary dermis and fibrinoid materials in the vessel walls and perivascular stroma ( Alavi et al., 2013 ; Georgesen et al., 2020 ). Fully developed lesions show thickening and hyalinization of vessel walls with endothelial edema and proliferation, along with intraluminal fibrin thrombi, dermal sclerosis, and scarring. Multiple biopsies could be necessary for definitive diagnosis; however, some experts suggest that multiple biopsies could complicate the healing of the ulceration ( Fig. 1 ; Alavi et al., 2013 ; Criado et al., 2011 ; Haunson et al., 2012 ).

Apart from routine histopathology, direct immunofluorescence (DIF) is used. DIF demonstrates immunoglobulin deposition (multiple immunoreactants, especially C3 and immunoglobulin [Ig] M, followed by IgA, and IgG), fibrin, and complement components, although DIF findings are thought to be nonspecific and nondiagnostic ( Criado et al., 2011 ; Khenifer et al., 2009 ; Nuttawong et al., 2021 ). In the literature, the incidence of positive DIF in patients with LV ranged from 42.9% to 100% ( Criado et al., 2014 ; Hsiao and Wu, 2010 ; Nuttawong et al., 2021 ; Schroeter et al., 1971 ; 1975 ). Older patients and more recent lesions (<6 months) had a significantly higher percentage of positive DIF results for LV ( Nuttawong et al., 2021 ).

Genetics

Several hereditary and acquired coagulation abnormalities are involved in LV, including polymorphisms in methylenetetrahydrofolate reductase (MTHFR), plasminogen activator inhibitor-1 (PAI-1), prothrombin, and factor V. The associations between LV and genetic abnormalities show geographical or ethnic differences. a recent systematic review investigating genetic variations identified that PAI-1-675 4G/5G was the most common, accounting for 85.26% of cases (n = 81 of 95), followed by PAI-1 A844G, MTHFR C677T, and MTHFR A1298C variants. Prothrombin G20210A and factor V G1691A were mainly present in patients with LV from Europe, North America, and South America ( Gao and Jin, 2021 ).

Clinical features

Patients with LV often have a history of painful recalcitrant ulcers and whitish scars near the ankles. Burning pain is a pathognomonic prodromal symptom of this entity. Physical examination might reveal lesions in different stages of evolution. The typical clinical appearance of LV consists of three main findings: livedo racemosa, skin ulcerations, and atrophie blanche ( Fig. 1 ; Alavi et al., 2013 ).

Livedo racemosa is distinguished by vivid, erythematous to purple, network-like lines, mainly due to abnormal perfusion of cutaneous microcirculation ( Fig. 2 ). Naturally, LV is not the only disease in which livedo racemosa can be seen; however, it is generally regarded clinically as an early manifestation of LV. Livedo reticularis and livedo racemosa (broken net pattern) are precursor lesions before ulceration. Fig. 2 Typical livedo racemosa lesions on the lower legs with vivid, erythematous to purple network-like lines. Fig 2

Purpuric macules, papules, or retiform or stellate purpura (especially considered as a hallmark lesion) are other important initial findings ( Fig. 3 ). They are often distributed on the ankles, dorsum of the feet, and the lower extremities and usually occur symmetrically. However, some studies also showed lesions on the upper extremities in a small proportion of patients ( Lee and Cho, 2020 ; Rujitharanawong et al., 2021 ). This is followed by acute-onset, painful, and small crusted ulcers. Ulcers characterize the active stage of the disease. Excruciating pain, causing difficulties in daily life, is a clue for early diagnosis because it precedes ulceration ( Vasudevan et al., 2016 ). Ulcers, characterized by a punched-out appearance on the perimalleolar area, heal within 3 to 4 months with atrophie blanche, small residual round or stellate porcelain-white atrophic scars surrounded by hyperpigmentation and telangiectasias ( Fig. 4 ; Alavi et al., 2013 ; Criado et al., 2011 ; Weishaupt et al., 2019 ). Fig. 3 Hallmark lesion of livedoid vasculopathy, with retiform or stellate purpura distributed to the ankles and painful and small crusted punched-out ulcers located on the perimalleolar area. Fig 3 Fig. 4 Atrophie blanche with small, residual, round or stellate, porcelain-white atrophic scars surrounded by hyperpigmentation and telangiectasias. Fig 4

Although systemic involvement is not a feature of idiopathic LV, peripheral nervous system involvement (paresthesia or hyperesthesia, mononeuritis multiplex) can be seen due to multifocal thrombosis and ischemia of the vasa nervorum and is the only known extracutaneous manifestation of LV ( Criado et al., 2011 ; Tubone et al., 2013 ; Vasudevan et al., 2016 ). A French observational study has revealed a high incidence of peripheral neuropathy (50% of patients), which has been described rarely in the existing literature ( Gan et al., 2012 ; Gardette et al., 2018 ). Due to the limitations of conventional diagnostic techniques (electromyelography, nerve biopsy), which mainly work with large nerve fibers, a diagnosis of peripheral neuropathy requires special investigations. Gardette et al. (2018) suggested that most patients with LV have neuropathic pain that persists after healing of ulcers despite a normal electromyelography; peripheral neuropathy is probably underestimated. Nerve biopsies also reveals an ischemic process, showing that LV is not only a cutaneous but also a peripheral neurological disease ( Gardette et al., 2018 ). Other systemic and multiorgan involvement might be present in secondary LV associated with autoimmune connective tissue disorders. A dermoscopic examination of LV could show central shallow crusted ulcers, ivory–white atrophic scar-like areas, pigment network or ivory–white structureless areas with a peripheral pigment network, and telangiectatic irregular, linear, and glomerular vessels ( Hu et al., 2017 ; Shen et al., 2019 ; Wen et al., 2020 ).

Diagnosis and differential diagnosis

The diagnostic criteria of LV are not well defined, and no treatment guidelines are available (except Delphi-consented expert recommendations; Alavi et al., 2013 ). A detailed history, dermatological examination, and laboratory work-up are essential for excluding other diseases in the differential diagnosis, demonstrating associated conditions, and, therefore, a diagnosis of LV.

When LV is clinically suspected, a skin biopsy should be taken to confirm the diagnosis. A fusiform incisional biopsy containing subcutaneous fat is the most appropriate biopsy. Alternatively, a 4 to 6 mm punch biopsy may be performed. The best place for a biopsy is the edge of a new ulcer; the biopsy specimen should contain 2 to 3 mm of marginal skin and the eventual ulcer ( Alavi et al., 2013 ).

A differential diagnosis of other common causes of atrophie blanche should be the first step in the clinical work-up. The most common diseases to be considered in the differential diagnosis are lower extremity chronic venous insufficiency, peripheral arterial vascular disease, and vasculitis. Along with clinical signs, abnormal arterial Doppler ultrasound findings and ankle-brachial index test support the diagnosis of peripheral artery diseases. Another main differential diagnosis is cutaneous polyarteritis nodosa, which produces similar cutaneous lesions on the legs. A proper skin biopsy can distinguish LV from vasculitis.

Despite all efforts, no associated factor can be detected in approximately 20% of all cases (idiopathic LV). In the remaining patients, connective tissue disorders, malignancy, hypercoagulable states, and thrombophilia are the most important associated factors ( Table 1 ; Fig. 1 ; Alavi et al., 2013 ; Weishaupt et al., 2019 ). Table 1 Differential diagnosis and their specific characteristic findings Table 1 Differential diagnosis Distinguishing features Chronic venous insufficiency Varicose veins, superficial telangiectasias, edema of the lower limbs, stasis dermatitis, ochre dermatitis, abnormal venous Doppler ultrasound findings Peripheral arterial disease Pale skin, claudication, painful ulcerations, abnormal arterial Doppler ultrasound findings, abnormal ankle-brachial index test Cutaneous polyarteritis nodosa Subcutaneous tender nodules on the legs, ulcerations, digital gangrene, medium vessel involvement, mononeuritis multiplex IgA vasculitis Age <10 y, organ involvement (joint, gastrointestinal and renal), IF; IgA Cutaneous leukocytoclastic angiitis Clinical and hematoxylin and eosin findings, such as IgA vasculitis; no organ involvement IgM/IgG vasculitis Urticaria ± necrotic/ulcerous lesions, IF; IgM/IgG Cryoglobulinemic vasculitis Cold exacerbation, Raynaud's phenomenon, acrocyanosis, renal involvement, IF; cryoglobulin II/III Recurrent macular vasculitis Recurrent and short-term hemorrhagic macules, hypergammaglobulinemia positive UV Normocomplementemic UV Hypocomplementemic UV Urticaria >24 h, postinflammatory pigmentation, ± hypocomplementemia Nodular vasculitis Dark red violet ± ulcerated nodules on the lateral/posterior tibia, lobular panniculitis, hypersensitivity to tuberculosis Eosinophilic granulomatosis with polyangiitis ANCA+, eosinophil-rich histopathology, respiratory (rhinitis, asthma history), renal (hematuria), neurological (neuropathy, mononeuritis multiplex), cardiac (eosinophilic cardiomyopathy) and gastrointestinal (polyposis, nausea, vomiting, abdominal pain) involvement Granulomatosis with polyangiitis p-ANCA or c-ANCA positive, retiform purpura-like lesions and reticulated ulcerations, pulmonary and renal disease (glomerulonephritis) Microscopic polyangiitis p-ANCA positivity, retiform purpura-like lesions and reticulated ulcerations, dermal granuloma, mononeuritis multiplex, pulmonary and renal disease Sneddon syndrome Livedo racemosa with cerebrovascular stroke Others in differential diagnosis of atrophie blanche Sickle cell disease, hydroxyurea ulcers, malignant atrophic papulosis, polycythemia vera, thalassemia, essential thrombocytosis, chronic myeloid leukemia ANCA, antineutrophil cytoplasmic antibody; IF, immunofluorescent; Ig, immunoglobulin; UV, urticarial vasculitis

Laboratory testing

When the diagnosis is confirmed histopathologically, further review of possible underlying diseases should be undertaken. Assessment, of course, should begin with a complete history, review of systems, and physical examination to assess findings suggestive of underlying diseases. Laboratory tests for thrombophilia are recommended in all patients ( Ishibashi et al., 2009 ; Sankar and Hinshaw, 2009 ; Winkelmann et al., 1974 ). Further examination, such as coagulating factors and their mutations, are required for hereditary or acquired thrombophilia.

Detailed laboratory research for connective tissue disorders, such as systemic lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis, scleroderma, and mixed connective tissue disease, should be performed in the presence of relevant findings suggestive of these diseases. In addition, Ig kappa and lambda chain levels, protein electrophoresis, and immunofixation should be performed when paraproteinemia or solid organ cancers are suspected. Again, in the presence of an underlying infection suspicion, tests for hepatitis and HIV infection should be performed ( Table 2 ). Table 2 Laboratory testing for livedoid vasculopathy Table 2 Hypercoagulable states/ fibrinolytic disorders/ thrombophilia Factor V Leiden and prothrombin G20210A mutation, protein C, protein S, anti-thrombin-III deficiency, PT/PTTK, aPTT, fibrinogen, D-dimer, lupus anticoagulant, lipoprotein (a), serum homocysteine, MTHFR-C677T polymorphism, prothrombin-G20210A mutation, serum fibrinopeptide A, levels of serum complements (C3, C4), fibrinogen, plasminogen-activator inhibitor activity, antiphospholipid antibodies, cryoglobulin, cold agglutinins and cryofibrinogen, Ig light chain (kappa and lambda) levels, serum folic acid, vitamin B12 and vitamin B6 levels Connective tissue diseases (systemic lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis, scleroderma, primary Sjogren's syndrome, polyarteritis nodosa, and undifferentiated connective tissue diseases) Levels of serum complements (C3, C4), ANCA, ANA, ENA, anti-Ro, anti-La, anti-CCP, rheumatoid factor, cryoglobulin, cryofibrinogen, plasminogen activator inhibitor, anti-beta-2 glycoprotein I, antiphospholipid antibodies (lupus anticoagulant), anticardiolipin antibodies (IgM and/or IgG), and IgM antiphosphatidylserine Malignancy Hematological (myeloproliferative disorders, paraproteinemia, multiple myeloma) and solid organ malignancies Ig light chain (kappa and lambda) levels, protein electrophoresis, immunofixation, lipoprotein (a) levels Infections Anti-streptolysin-O, throat culture, hepatitis B, hepatitis C, enzyme-linked immunosorbent assay for HIV, COVID-19, swab wound culture, and tissue cultures Conditions associated with stasis (chronic venous hypertension of the limbs, varicose veins) Venous Doppler ultrasound, arterial Doppler ultrasound, ankle-brachial/toe-brachial pressure index, venous duplex imaging, plethysmography, and transcutaneous oximetry cardiovascular surgery consultation Assessing tissue ischemia Transcutaneous oxygen pressure or partial pressure of oxygen by transcutaneous oximetry adjacent to the ulcer, Doppler flowmetry, laser Doppler perfusion imaging, and microlymphography Pregnancy Urine human chorionic gonadotropin Other Complete blood count, comprehensive metabolic panel, urinalysis, erythrocyte sedimentation rate, C-reactive protein, peripheral smear, fecal occult blood ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; aPTT, activated partial thromboplastin time; CCP, cyclic citrullinated peptide antibodies; ENA, extractable nuclear antigen antibody; Ig, immunoglobulin; MTHFR, methylenetetrahydrofolate reductase; PT, prothrombin time; PTTK, partial thromboplastin time with kaolin

Treatment

Treatment of LV is very challenging for physicians. Because the incidence of LV is relatively low, there are no large series of studies on its treatment. Therefore, the level of evidence is not high, and treatment recommendations are generally based on case series, small clinical trials, or expert recommendations. No single therapeutic approach is effective for all patients. Furthermore, there are no predictive clinical or biologic indicators for the severity or frequency of LV flares. For this reason, many options are often used in combination. Moreover, there is no fixed endpoint for treatment in patients who respond to treatment. Once the ulcer has healed, treatment may be discontinued; however, long-term treatment may be necessary to maintain healing. Treatment selection can be based on cost, adherence, patient comorbidities, and clinical experience. The main treatment options are presented in Table 3 . Our approach is reviewed herein, and the therapeutic algorithmic approach is presented in Figure 5 . Table 3 Therapeutic options of livedoid vasculopathy Table 3 Treatment (reference) Mechanism of action Dose Side effects Antiplatelets Aspirin (acetylsalicylic acid) ( Acland et al., 1999 ; Castillo-Martínez et al., 2014 ; Criado et al., 2013 ; Drucker and Duncan, 1982 ; Gan et al., 2012 ; El Khoury et al., 2012 ; Krueger et al., 2020 ; Lee et al., 2003 ; Okada et al., 2008 ) Cyclooxygenase inhibitor; suppresses thromboxane A2 and prostaglandin I2; promotes vasodilation; prevents platelet aggregation and thrombus formation; improves ulcer healing 75–325 mg, higher doses (up to 325 mg, 3 × 1 daily) offering better results Angioedema, urticaria, gastrointestinal bleeding, Reye's syndrome, salicylism (central nervous system, tinnitus) Pentoxifylline ( Criado et al., 2021 ; Feng et al., 2014 ; Gan et al., 2012 ; Krueger et al., 2020 ; Lee et al., 2003 ; Marzano et al., 2003 ; Meiss et al., 2006 ; Sams, 1988 ; Song et al., 2020 ; Yong et al., 2012 ) Competitive nonselective phosphodiesterase inhibitor; reduces inflammation; decreases blood viscosity; modifies red blood cell structure to reduce exocytosis; increases the inflow circulation; reduces platelet aggregation and thrombus formation 400 mg every 3 × 1 daily Dyspepsia, nausea, vomiting, abnormal liver function, alopecia Dipyridamole ( Agirbasli et al., 2011 ; Drucker and Duncan, 1982 ; Krueger et al., 2020 ) Phosphodiesterase inhibitor; inhibits the synthesis of thromboxane A2; stimulates release of prostaglandin I2; inhibits both adenosine deaminase and phosphodiesterase, preventing the degradation of cAMP (inhibitor of platelet function and aggregation) Initial: Dose of 50 mg, twice daily (up to75 mg 4 × 1) Bleeding, dizziness Clopidogrel ( Kunzler and Chong, 2018 ) Antiplatelet agent; inhibits prostaglandin synthesis; irreversibly binds to P2Y12 ADP receptors on platelets and prevents platelet aggregation 75 mg once daily Hemorrhage, vomiting, pancytopenia, thrombotic thrombocytopenic purpura, hypersensitivity reactions Ticlopidine ( Hegemann et al., 2002 ; Okada et al., 2008 ) Prodrug that is metabolized to an active form; blocks ADP receptor that is involved in GP IIb/IIIa receptor activation leading to platelet aggregation 250 mg twice daily Aplastic anemia, thrombotic thrombocytopenia purpura, black-box warning of neutropenia, bleeding, hepatic impairment Buflomedil hydrochloride ( Criado et al., 2011 ) Antiplatelet effect; nonspecific calcium channel antagonist and alpha-blocker; increases inflow circulation Oral 150 mg, 3–4 × daily or 300 mg twice daily Flushing, headache, vertigo, dizziness, gastrointestinal discomfort Beraprost sodium ( Tsutsui et al., 1996 ) Analog of PGI2; stable, orally active prostacyclin analog with vasodilatory, antiplatelet and cytoprotective effects 120 μg/day initially and at a dose of 60 μg/d subsequently Headache, flushing, diarrhea, leg pain, and nausea Abciximab ( Vasudevan et al., 2016 ) Monoclonal antiglycoprotein IIb/IIIa receptor antibody for glycoprotein IIb/IIIa receptor of human platelets; inhibits platelet aggregation by preventing binding of fibrinogen, von Willebrand factor, and other adhesive molecules 0.25 mg/kg IV bolus followed by continuous IV infusion of 0.125 μg/kg/min for 12 hr Bleeding, thrombocytopenia Sarpogrelate hydrochloride ( Osada et al., 2010 ; Vasudevan et al., 2016 ) Antagonist of 5-hydroxytryptamine 2A receptor (serotonin); antiplatelet and vasodilator effects Orally 300 mg/day Hemorrhage, thrombocytopenia, agranulocytosis, jaundice Anticoagulant Warfarin ( Browning and Callen, 2006 ; Di Giacomo et al., 2010 ; Kavala et al., 2008 ; Nakamura et al., 2011 ; Nakayama et al., 2017 ; Noda et al., 2011 ; Osada et al, 2010 ; Saoji and Madke, 2017 ; Vieira et al., 2016 ; Yoshioka et al., 2018 ) Vitamin K antagonist; inhibits vitamin-K dependent synthesis of biologically active forms of various clotting factors in addition to several regulatory factors; increases fibrinolytic activity Oral/IV; 2–5 mg once daily for 1–2 days, then adjust dose based on international normalized ratio (maintained between 2 and 3) Maintenance: 2–10 mg oral/IV once daily Teratogen, bleeding, jaundice, necrosis, purple toe syndrome, osteoporosis, valve and artery calcification, and drug interactions Heparin ( Abou Rahal et al., 2012 ; Di Giacomo et al., 2010 ; Francès and Barete, 2004 ) Decreases blood viscosity; increases fibrinolytic activity; increases activity of tissue plasminogen activator Dose of 5000 U/12 hr, subcutaneously Bleeding, thrombocytopenia LMWH (enoxaparin, dalteparin, nadroparin) ( Abou Rahal et al., 2012 ; Cardoso et al., 2007 ; Di Giacomo et al., 2010 ; Francès and Barete, 2004 ; Goerge et al., 2010 ; Hairston et al., 2003 ) Decreases blood viscosity; increases fibrinolytic activity Enoxaparin 40 mg/day or 100 IU/g per injection bidaily, dalteparin sodium 5000 IU/day, subcutaneously Late hypersensitivity, injection site reactions, increase in liver enzymes Rivaroxaban ( Chen et al., 2017 ; Drabik et al., 2014 ; Drerup and Goerge, 2017 ; Evans et al., 2015 ; Franco Marques and Criado, 2018 ; Jiménez-Gallo et al., 2018 ; Kerk et al., 2013 ; Lee and Cho, 2020 ; Lee and Kim, 2016 ; Leisenring et al., 2020 ; Miguel et al., 2020 ; Weishaupt et al., 2016 ; 2019; Winchester et al., 2015 ) Direct inhibitor of factor Xa; new LMWH; decreases blood viscosity; increases fibrinolytic activity 10 mg bidaily, orally Hypermenorrhea, nose bleeding, bleeding tendency during dental procedures, and hemarthrosis Other vitamin K antagonists (preprohormone, acenocoumarin, fluindione) ( Francès and Barete, 2004 ) Decreases blood viscosity; increases fibrinolytic activity Require monitoring international normalized ratio (maintained between 2–3) Bleeding tendency Sulodexide ( Song et al., 2020 ) Highly purified mixture of glycosaminoglycans, including dermatan sulfate and LMWH Oral 250 lipasemic units 3 × 1 daily Transient gastrointestinal intolerance, nausea, dyspepsia Fibrinolytics Recombinant tissue plasminogen activator ( Agirbasli et al., 2011 ; Antunes et al., 2010 ; Deng et al., 2006 ; Johnson et al., 1995 ; Klein and Pittelkow, 1992 ; Murrell et al., 1995 ) Fibrinolysis of microvascular thrombi; restores the circulation; promotes wound healing 10 mg IV every 4 hr/day, 14 day Bleeding, allergic reactions Danazol/stanozolol ( Acland et al., 1999 ; Criado et al., 2015; Feng et al., 2014 ; Hsiao and Chiu, 1996 ; 1997 ; Rizzo et al., 1986 ; Wakelin et al., 1998 ) Synthetic steroids and pituitary gonadotropin inhibitors; have fibrinolytic activity Danazol: 200 mg/day or 4 mg/kg/day) for a short duration of 4–12 week Stanozolol: 4 mg/day Hirsutism, acne, steroid-like side effects, alopecia, menstrual disturbances, clitoral hypertrophy Vasodilators Nifedipine ( Purcell and Hayes, 1986 ; Vasudevan et al., 2016 ) Dihydropyridine calcium channel blocker; reduces vasospasm; decreases peripheral arterial vascular resistance; increases supply of oxygen 10–20 mg 3 × 1 per day Hypotension, sinus node dysfunction, atrioventricular node dysfunction, reflex tachycardia Cilostazol ( Mendiratta et al., 2016 ) Quinolinone derivative; phosphodiesterase III inhibitor; antiplatelet agent and vasodilator 100 mg twice daily Headache, diarrhea, tachycardia, hypotension, cardiac arrhythmias Nicotinic acid (Winkelman, 1974) Niacin is a B3 vitamin; decreases levels of very low-density lipoproteins and low-density lipoproteins, while increasing levels of high-density lipoproteins 1–3 × daily Severe prolonged hypotension Alprostadil-alpha (Prostaglandin E1) ( Kawakami et al., 2007 ; Mofarrah et al., 2013 ) Direct effect on vascular smooth muscle; causes vasodilation 60 μg/day over 3 hr for 5 days, followed by a monthly infusion of 60 μg over 3 hr Apnea, bradycardia, pyrexia, hypotension İloprost ( Magy et al., 2002 ) Synthetic analog of prostacyclin PGI2; inhibits ADP, thrombin, and collagen-induced aggregation of platelets IV via infusion pump at a rate of 0.5 ng/kg/min for 6–8 h/day (maximum tolerated dose of 2 ng/kg/min) Hypotension, headache, nausea, vomiting, and diarrhea Ketanserin ( Rustin et al., 1989 ) S2 serotonergic receptor blocker; prevents vasoconstrictive effect of serotonin; increases cutaneous blood flow Dose of 20 mg 3 × daily Drowsiness, fatigue, headache, sleep disturbances Anti-inflammatory Colchicine ( Gan et al., 2012 ; Lee et al., 2003 ; Vasudevan et al., 2016 ) Alkaloid; inhibition of inflammation caused by tubulin disruption; anti-inflammatory effects with neutrophil inhibition Oral 0.5 mg, 2 × 3 × daily Gastrointestinal disturbance, including abdominal pain, nausea, vomiting, diarrhea Dapsone ( Acland et al., 1999 ; Gan et al., 2012 ; Irani-Hakime et al., 2008 ; Micielli and Alavi, 2018; Winkelman, 1972) Sulfone drug; anti-inflammatory effects with neutrophil inhibition; immunosuppressive and antibacterial properties Oral doses of 50–100 mg/day Nasal congestion, syncope, anemia, hallucinations Sulfasalazine ( Bisalbutra and Kullavanijaya, 1993 ; Micielli and Alavi, 2018) Sulphapyridine metabolite; anti-inflammatory and/or immunomodulatory properties; inhibition of platelet aggregation by 5-aminosalicylic acid prevents cytokine release from mononuclear cells 500 mg, 3 × 1 daily, orally Headache, facial edema, paresthesia of the lips, nausea, rash, itchiness, metallic taste Doxycycline ( Keller et al., 2008 ) Second-generation tetracycline antibiotic; anti-inflammatory and antimicrobial, bacteriostatic effects by inhibition of protein synthesis Dose of 100 mg twice daily Tooth enamel hypoplasia, yellow–gray discoloration of teeth, gastrointestinal irritation, esophagitis Hydroxychloroquine ( Gan et al., 2012 ; Irani-Hakime et al., 2008 ; Keller et al., 2008 ; Vasudevan et al., 2016 ) Aminoquinoline; affects function of lysosomes in humans; inhibits antigen presentation of the cell; reduces inflammatory response Up to 0.6 mg/kg/day Headache, drowsiness, visual disturbances, convulsions, rhythm, conduction disorders including QT prolongation, torsades de pointes, ventricular tachycardia, ventricular fibrillation Immunosuppressants Prednisolone ( Alavi et al., 2013 ; Criado et al., 2011 ; Gan et al., 2012 ; Marzano et al., 2003 ; Micieli et al., 2018) Anti-inflammatory action; antifibrinolytic effect; immunosuppressive effect 0.5–1 mg/kg/day (prednisolone or equivalent) Steroid side effects Azathioprine ( Alavi et al., 2013 ; Criado et al., 2011 ; Gan et al., 2012 ; Micieli et al., 2018) Prodrug of 6-mercaptopurine; inhibits purine synthesis along with inhibition of B and T cells 2–3 mg/kg/day Bone marrow hypoplasia, hepatotoxicity, infection Cyclophosphamide ( Alavi et al., 2013 ; Criado et al., 2011 ; Gan et al., 2012 ; Micieli et al., 2018) Alkylating agent; cytotoxic effect due to cross-linking of strands of DNA and RNA; inhibition of protein synthesis; immunosuppressive effect 1.5–2.5 mg/kg/day Neutropenia, alopecia, nausea, vomiting, diarrhea, sterility, birth defects, mutations, cancer Cyclosporine ( Alavi et al., 2013 ; Criado et al., 2011 ; Micieli et al., 2018) Calcineurin inhibitor; potent immunomodulatory agent; suppresses lymphocyte activity; inhibits expression of tissue factor of monocytes, which is a vital component in triggering the coagulation cascade 3–5 mg/kg/day Hypertrichosis, gingival hyperplasia, nephrotoxicity, hypertension Supplements Folic acid ( Anderson et al., 2013 ; Errichetti and Stinco, 2016 ; Meiss et al., 2006 ) Required for homocysteine remethylation; necessary to maintain adequate plasma homocysteine and serum folate levels 5 mg/day Abdominal cramps, diarrhea, sleep disorders, irritability, confusion, stomach upset Vitamin B12/B6 ( Anderson et al., 2013 ; Errichetti and Stinco, 2016 ; Meiss et al., 2006 ) Additional supplementation along with folic acid Vitamin B6 (1500 μg/day) and vitamin B12 Nausea, stomach upset, diarrhea, drowsiness, flushing, numbness/tingling Miscellaneous Intravenous immunoglobulin ( Amital et al., 2000 ; Bounfour et al., 2013 ; Kim et al., 2015 ; Kofler et al., 2021 ; Kreuter et al., 2004 ; Monshi et al., 2014 ; Oravec et al., 1995 ; Ozden et al., 2020 ; Pitarch et al., 2005 ; Ravat et al., 2002 ; Tuchinda et al., 2011 ) Acts by inhibiting Fc receptor function in macrophages, T cells, and B cells, leading to decreased cytokine production; reduces immune complex deposition in small vessels; inhibits thromboxane synthetase; decreases vasoconstriction Monthly infusions in the dose of 0.4–2 g/kg over 2–3 consecutive days Allergic reactions, headache, flushing, chills, myalgia, wheezing, tachycardia, hypotension Hyperbaric oxygen ( Banham, 2013 ; Bhutani et al., 2012 ; Bollmann et al., 2011 ; Fernandes, 2009 ; Juan et al., 2006 ; Ray et al., 2015 ; Verma, 2013 ; Yang et al., 2003 ) Enhances tissue oxygenation and microvascular perfusion by stimulating nitric oxide synthesis; accelerates angiogenesis and fibrinolysis; accelerates fibroblast proliferation; diminishes tissue reperfusion injury; increases growth of granulation tissue; bacteriostatic and bactericidal effects Pure oxygen or 100% 1.5–2 hr, 1–3 × daily Lung damage, changes in vision, oxygen poisoning Psoralen plus ultraviolet A ( Choi and Hann, 1999 ; Lee et al., 2001 ; Tuchinda et al., 2005 ) Decreases ability of lymphocytes to respond to cytokine production; induces release of immunosuppressive factors 2–3 × per week Sunburn-like reaction, phototoxic erythema, skin ageing and skin cancer Rituximab ( Zeni et al., 2008 ) Monoclonal anti-CD20 antibody 1.0 g, two infusions, 14 days apart Neonatal harm, infection risk, severe immunosuppression Antitumor necrosis factor (etanercept) ( Gao and Jin, 2020 ) Anti-inflammatory properties; act mainly by close interaction between various inflammatory cytokines and coagulation 25–50 mg once a week for 12 consecutive weeks Infection risk, immunosuppression ADP, adenosine diphosphate; cAMP; IV, intervenous; LMWH, low molecular weight heparin; PGI2, prostaglandin I2 Fig. 5 Algorithmic therapeutic approach of livedoid vasculopathy. Fig 5

Although the best approach to treatment is unclear, general measures (e.g., wound care, smoking cessation, compression, and pain management) are important components of LV therapy along with pharmacological treatment. Wound care should include maintaining a moist wound environment and controlling superinfection. Patients should be encouraged to stop smoking because of the negative effects of smoking on wound healing. Compression therapy is also helpful in patients with venous insufficiency. Improvement may be due to the stimulating effect of compression on fibrinolytic activity and controlling edema. Pain secondary to livedoid vasculopathy can be severe. Nonsteroidal anti-inflammatory drugs, such as indomethacin or acetaminophen, can be used. Tricyclic antidepressants, gabapentin, pregabalin, or carbamazepine may be preferred for neuropathic pain and are valuable for patients with persistent painful ulcerations ( Alavi et al., 2013 ; Micieli and Alavi, 2018 ).

The first-line therapeutic step is antiplatelet therapy (aspirin, dipyridamole, and pentoxifylline). Aspirin (300 mg once daily) is preferred, especially as the initial therapy for patients without an identified thrombophilia and/or with sickle cell trait. Tolerability, wide availability, and low cost are important advantages of this compound. Dipyridamole and pentoxifylline (600 mg twice daily) can be favored in combination with aspirin in unresponsive cases or alone in patients who cannot tolerate aspirin. In patients with identified thrombophilia and/or without significant improvement after antiplatelet treatment, anticoagulants can be used. Low molecular weight heparin (1 mg/kg/d) or rivaroxaban (2 × 15 mg in the first week, then continue with 20 mg once daily) are typically used at our center. Anticoagulants were the most reported monotherapy in a recent systematic review by Micieli and Alavi (2018) . Rivaroxaban is often the treatment of choice in recent years due to the advantage of oral administration and the unnecessity of international normalized ratio follow-up, which increases patient compliance.

Anabolic steroids (prednisolone and equivalents, danazol 4 mg/kg/d) were the second most used and effective treatment in clinical trials. They inhibit coagulation while increasing fibrinolysis. They can be the next step, especially in patients with connective tissue diseases, hyperfibrinogenemia, and other occlusive conditions. Systemic steroids can also be added to the main treatment to achieve rapid disease control at any timepoint.

In resistant cases, preference for therapeutic choices is based on availability, clinical experience, and patient-related factors (comorbidities, age, sex, compliance). Intravenous Ig, hyperbaric oxygen treatment (1.5-2-hour sessions, three times daily for 3-4 weeks) and fibrinolytics (recombinant tissue plasminogen activator, 10 mg/d for 14 days) have also been reported to be effective alternatives. These treatments would be more suitable for refractory LV due to high cost and difficulties in patient compliance. All other therapeutic options are summarized in Table 3 . Hydroxychloroquine in patients with systemic lupus erythematosus and antiphospholipid antibody syndrome, and colchicine in patients with vasculitis can be reasonable options in combination with antiplatelet and/or anticoagulant therapies. Vasodilators (used as maximum tolerated dose), anti-inflammatory agents, immunosuppressives, and psoralen-ultraviolet A could be used as third-line options. Vitamin supplements, especially folic acid and vitamin B12/B6, are required for homocysteine remethylation; thus, they can be added to treatment. All these agents are used often in combination with antiplatelets and anticoagulants ( Alavi et al., 2013 ; Micieli and Alavi, 2018 ).

Conclusion

LV is associated with a variety of underlying conditions, and no single etiology has been identified. Since the therapeutic approach should be modified according to etiopathogenetic mechanisms, possible systemic associations should be investigated. Several therapeutic options with different success rates are being used. However, randomized controlled trials with a high evidence level should be performed to determine the best therapeutic approach in the treatment of LV. Furthermore, a multidisciplinary approach is necessary for effective and proper treatment.

Conflicts of interest

None.

Funding

None.

Study approval

N/A

References

Abou Rahal J Ishak RS Otrock ZK Kibbi AG Taher AT Livedoid vasculopathy in a patient with lupus anticoagulant and MTHFR mutation: Treatment with low-molecular-weight heparin J Thromb Thrombolysis 34 4 2012 541 544 22592843 10.1007/s11239-012-0743-5

Acland KM Darvay A Wakelin SH Russell-Jones R Livedoid vasculitis: A manifestation of the antiphospholipid syndrome? Br J Dermatol 140 1 1999 131 135 10215783 10.1046/j.1365-2133.1999.02622.x

Agirbasli M Eren M Eren F Murphy SB Serdar ZA Seckin D Enhanced functional stability of plasminogen activator inhibitor-1 in patients with livedoid vasculopathy J Thromb Thrombolysis 32 1 2011 59 63 21311952 10.1007/s11239-011-0556-y

Alavi A Hafner J Dutz JP Mayer D Sibbald RG Criado PR Livedoid vasculopathy: An in-depth analysis using a modified Delphi approach J Am Acad Dermatol 69 6 2013 1033 1042 e1 24028907 10.1016/j.jaad.2013.07.019

Amato L Chiarini C Berti S Massi D Fabbri P. Idiopathic atrophie blanche Skinmed 5 2006 151 154 16687988 10.1111/j.1540-9740.2006.04541.x

Amital H Levy Y Shoenfeld Y. Use of intravenous immunoglobulin in livedo vasculitis Clin Exp Rheumatol 18 2000 404 406 10895384

Anderson CA Beresford SA McLerran D Lampe JW Deeb S Feng Z Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: Results from a crossover trial Mol Nutr Food Res 57 2013 637 644 23456769 10.1002/mnfr.201200108 PMC4132693

Antunes J Filipe P André M Fraga A Miltenyi G Marques Gomes M. Livedoid vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity (4G/4G) and prothrombin G20210A heterozygosity: Response to t-PA therapy Acta Derm Venereol 90 1 2010 91 92 20107738 10.2340/00015555-0760

Banham ND. Livedoid vasculopathy successfully treated with hyperbaric oxygen Diving Hyperb Med 43 1 2013 35 36 23508660

Bard JW Winkelmann RK. Livedo vasculitis. Segmental hyalinizing vasculitis of the dermis Arch Dermatol 96 1967 489 499 6054223 10.1001/archderm.96.5.489

Bhutani S Verma R Verghese G. Livedoid vasculopathy managed with hyperbaric oxygen therapy Med J Armed Forces India 68 4 2012 389 391 24532913 10.1016/j.mjafi.2012.01.002 PMC3862953

Bisalbutra P Kullavanijaya P. Sulfasalazine in atrophie blanche J Am Acad Dermatol 28 2 1993 275 276 Pt 1 8094403 10.1016/s0190-9622(08)81156-5

Bollmann PW Shimada AK Michalany NS Manhani AR Giglio AD. Livedoid vasculopathy: fast involution after anticoagulant and hyperbaric oxygen therapy Einstein (Sao Paulo) 9 2 2011 212 215 26760818 10.1590/S1679-45082011RC1676

Bounfour T Bouaziz JD Bézier M Petit A Viguier M Rybojad M Bagot M. Intravenous immunoglobulins in difficult-to-treat ulcerated livedoid vasculopathy: Five cases and a literature review Int J Dermatol 52 9 2013 1135 1139 23488633 10.1111/j.1365-4632.2012.05826.x

Browning CE Callen JP. Warfarin therapy for livedoid vasculopathy associated with cryofibrinogenemia and hyperhomocysteinemia Arch Dermatol 142 1 2006 75 78 16415390 10.1001/archderm.142.1.75

Cardoso R Gonçalo M Tellechea O Maia R Borges C Silva JA Livedoid vasculopathy and hypercoagulability in a patient with primary Sjogren's syndrome Int J Dermatol 46 4 2007 431 434 17442092 10.1111/j.1365-4632.2007.03229.x

Castillo-Martínez C Moncada B Valdés-Rodríguez R González FJ. Livedoid vasculopathy (LV) associated with sticky platelets syndrome type 3 (SPS type 3) and enhanced activity of plasminogen activator inhibitor (PAI-1) anomalies Int J Dermatol 53 12 2014 1495 1497 25131360 10.1111/j.1365-4632.2012.05786.x

Chen W Fan L Wang Y Deng X. Treatment application of rivaroxaban in Chinese patients with livedoid vasculopathy J Pain Res 10 2017 621 624 28360530 10.2147/JPR.S133462 PMC5364015

Choi HJ Hann SK. Livedo reticularis and livedoid vasculitis responding to PUVA therapy J Am Acad Dermatol 40 2 1999 204 207 Pt 1 10025746 10.1016/s0190-9622(99)70189-1

Criado PR Rivitti EA Sotto MN Valente NY Aoki V Carvalho JF Livedoid vasculopathy: An intringuing cutaneous disease An Bras Dermatol 86 5 2011 961 977 22147037 10.1590/s0365-05962011000500015

Criado PR Alavi A Halpern I Sotto MN Kirsner RS. Unilateral livedoid vasculopathy associated with involutional phase of cutaneous infantile hemangioma: The connection to coagulation disorders Int J Low Extrem Wounds 12 4 2013 306 309 24043683 10.1177/1534734613502049

Criado PR Di Giacomo TH Souza DP Santos DV Aoki V. Direct immunofluorescence findings and thrombophilic factors in livedoid vasculopathy: how do they correlate? Clin Exp Dermatol 39 2014 66 68 23692592 10.1111/ced.12157

Criado PR Pagliari C Morita TCAB Marques GF Pincelli TPH Valente NYS Livedoid vasculopathy in 75 Brazilian patients in a single-center institution: Clinical, histopathological and therapy evaluation Dermatol Ther 34 2 2021 e14810 33496999 10.1111/dth.14810

Drabik A Hillgruber C Goerge T. A phase II multicenter trial with rivaroxaban in the treatment of livedoid vasculopathy assessing pain on a visual analog scale JMIR Res Protoc 3 4 2014 e73 25500152 10.2196/resprot.3640 PMC4275467

Deng A Gocke CD Hess J Heyman M Paltiel M Gaspari A. Livedoid vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity (4G/4G) treated successfully with tissue plasminogen activator Arch Dermatol 142 11 2006 1466 1469 17116837 10.1001/archderm.142.11.1466

Di Giacomo TB Hussein TP Souza DG Criado PR. Frequency of thrombophilia determinant factors in patients with livedoid vasculopathy and treatment with anticoagulant drugs–A prospective study J Eur Acad Dermatol Venereol 24 11 2010 1340 1346 20337814 10.1111/j.1468-3083.2010.03646.x

Drerup C Goerge T. Prevention of livedoid vasculopathy recurrence by prolonged administration of rivaroxaban J Eur Acad Dermatol Venereol 31 12 2017 e532 28609556 10.1111/jdv.14404

Drucker CR Duncan WC. Antiplatelet therapy in atrophie blanche and livedo vasculitis J Am Acad Dermatol 7 3 1982 359 363 7130497 10.1016/s0190-9622(82)70123-9

El Khoury J Taher A Kurban M Kibbi AG Abbas O Livedoid vasculopathy associated with sickle cell trait: Significant improvement on aspirin treatment Int Wound J 9 3 2012 344 347 22044499 10.1111/j.1742-481X.2011.00882.x PMC7950644

Errichetti E Stinco G. Recalcitrant livedoid vasculopathy associated with hyperhomocysteinaemia responding to folic acid and vitamins B6/B12 supplementation Acta Derm Venereol 96 7 2016 987 988 27001413 10.2340/00015555-2416

Evans JM Jensen JD Sami N. Successful treatment of livedoid vasculopathy with rivaroxaban JAAD Case Rep 1 6 2015 340 341 27051773 10.1016/j.jdcr.2015.08.002 PMC4809376

Feng S Su W Jin P Shao C Livedoid vasculopathy: clinical features and treatment in 24 Chinese patients Acta Derm Venereol 94 5 2014 574 578 24352295 10.2340/00015555-1711

Fernandes TD. Hyperbaric medicine Acta Med Port 22 2009 323 334 19909659

Francès C Barete S. Difficult management of livedoid vasculopathy Arch Dermatol 140 8 2004 1011 15313824 10.1001/archderm.140.8.1011

Franco Marques G Criado PR Alves Batista Morita TC, Cajas García MS. The management of livedoid vasculopathy focused on direct oral anticoagulants (DOACs): Four case reports successfully treated with rivaroxaban Int J Dermatol 57 6 2018 732 741 29663354 10.1111/ijd.13997

Freitas TQ Halpern I Criado PR. Livedoid vasculopathy: A compelling diagnosis Autops Case Rep 8 3 2018 e2018034 10.4322/acr.2018.034 PMC6066260 30101138

Gan EY Tang MB Tan SH Chua SH Tan AW. A ten-year retrospective study on livedo vasculopathy in Asian patients Ann Acad Med Singapore 41 2012 400 406 23052434

Gao Y Jin H. Livedoid vasculopathy and its association with genetic variants: A systematic review Int Wound J 2021 [Epub ahead of publication] 10.1111/iwj.13563 PMC8450804 33686673

Gao Y Jin H. Efficacy of an anti-TNF-alpha agent in refractory livedoid vasculopathy: A retrospective analysis J Dermatol Treat 2020 1 6 10.1080/09546634.2020.1737634 32116074

Gardette E Moguelet P Bouaziz JD Lipsker D Dereure O Le Pelletier F Livedoid vasculopathy: A French observational study including therapeutic options Acta Derm Venereol 98 9 2018 842 847 29738044 10.2340/00015555-2965

Georgesen C Fox LP Harp J. Retiform purpura: A diagnostic approach J Am Acad Dermatol 82 4 2020 783 796 31479689 10.1016/j.jaad.2019.07.112

Goerge T Weishaupt C Metze D Nowak-Göttl U Sunderkötter C Steinhoff M Livedoid vasculopathy in a pediatric patient with elevated lipoprotein(a) levels: Prompt response to continuous low-molecular-weight heparin Arch Dermatol 146 8 2010 927 928 20713839 10.1001/archdermatol.2010.177

Gonzalez-Santiago TM Davis MD. Update of management of connective tissue diseases: Livedoid vasculopathy Dermatol Ther 25 2012 183 194 22741937 10.1111/j.1529-8019.2012.01490.x

Hairston BR Davis MD Gibson LE Drage LA. Treatment of livedoid vasculopathy with low-molecular-weight heparin: Report of 2 cases Arch Dermatol 139 2003 987 990 12925383 10.1001/archderm.139.8.987

Hairston BR Davis MD Pittelkow MR Ahmed I. Livedoid vasculopathy: Further evidence for procoagulant pathogenesis Arch Dermatol 142 11 2006 1413 1418 17116831 10.1001/archderm.142.11.1413

Haunson GT Judy DW Prall NC Miller RA. Livedoid vasculopathy: Review of pathogenesis, clinical presentation, diagnostic workup, and treatment Cutis 90 6 2012 302 306 23409480

Hegemann B Helmbold P Marsch WC. Livedoid vasculitis with ulcerations: The role of antithrombin III deficiency and its therapeutic consequences Arch Dermatol 138 6 2002 841 842 12056979 10.1001/archderm.138.6.841

Hesse G Kutzner H. Therapeutic use of low molecular weight heparin for capillaritis alba Phlebologie 37 2008 259 265

Hsiao GH Chiu HC. Livedoid vasculitis. Response to low-dose danazol Arch Dermatol 132 1996 749 751 8678566 10.1001/archderm.1996.03890310027003

Hsiao GH Chiu HC. Low-dose danazol in the treatment of livedoid vasculitis Dermatology 194 1997 251 255 9187843 10.1159/000246113

Hsiao PF Wu YH. Distinct pattern of direct immunofluorescence in livedoid vasculopathy Am J Dermatopathol 32 2010 240 243 20075710 10.1097/DAD.0b013e3181b7bf90

Hu SC Chen GS Lin CL Cheng YC Lin YS. Dermoscopic features of livedoid vasculopathy Medicine (Baltimore) 96 11 2017 e6284 28296736 10.1097/MD.0000000000006284 PMC5369891

Irani-Hakime NA Stephan F Kreidy R Jureidini I Almawi WY. Livedoid vasculopathy associated with combined prothrombin G20210A and factor V (Leiden) heterozygosity and MTHFR C677T homozygosity J Thromb Thrombolysis 26 1 2008 31 34 18360788 10.1007/s11239-008-0214-1

Ishibashi M Miyamoto J Nagasaka T Chen KR. Livedoid vasculopathy with underlying subcutaneous necrotizing venulitis in an asymptomatic hepatitis B virus carrier: Is livedoid vasculopathy a true nonvasculitic disorder? Am J Dermatopathol 31 3 2009 293 296 19384073 10.1097/DAD.0b013e31819560aa

Jiménez-Gallo D Villegas-Romero I Rodríguez-Mateos ME Linares-Barrios M. Treatment of livedoid vasculopathy with rivaroxaban: A potential use of new oral anticoagulants for dermatologists Actas Dermosifiliogr (Engl Ed) 109 3 2018 278 281 29074145 10.1016/j.ad.2017.07.015

Johnson DW Hawley CM Strutton G Gibbs HH. Dramatic response of livedoid vasculitis to tissue plasminogen activator (tPA) Aust N Z J Med 25 4 1995 370 371 8540885 10.1111/j.1445-5994.1995.tb01909.x

Juan WH Chan YS Lee JC Yang LC Hong HS Yang CH. Livedoid vasculopathy: Long-term follow-up results following hyperbaric oxygen therapy Br J Dermatol 154 2006 251 255 16433793 10.1111/j.1365-2133.2005.06843.x

Kavala M Kocaturk E Zindanci I Turkoglu Z Altintas S. A case of livedoid vasculopathy associated with factor V Leiden mutation: Successful treatment with oral warfarin J Dermatolog Treat 19 2008 121 123 18484430 10.1080/09546630701670305

Kawakami T Kawasaki K Mizoguchi M Soma Y. Therapeutic effect of lipoprostaglandin E1 on livedoid vasculitis associated with essential cryoglobulinaemia Br J Dermatol 157 5 2007 1051 1053 17725674 10.1111/j.1365-2133.2007.08143.x

Keller MS Lee J Webster GF. Livedoid thrombotic vasculopathy responding to doxycycline therapy J Clin Aesthet Dermatol 1 2008 22 24 PMC3016933 21212844

Kerk N Drabik A Luger TA Schneider SW Goerge T. Rivaroxaban prevents painful cutaneous infarctions in livedoid vasculopathy Br J Dermatol 168 4 2013 898 899 23106384 10.1111/bjd.12100

Khenifer S Thomas L Balme B Dalle S. Livedoid vasculitis associated with a double heterozygous Factor V Leiden and prothrombin G20210A gene mutation Clin Exp Dermatol 34 2009 e811 e813 19793098 10.1111/j.1365-2230.2009.03541.x

Kim EJ Yoon SY Park HS Yoon HS Cho S. Pulsed intravenous immunoglobulin therapy in refractory ulcerated livedoid vasculopathy: Seven cases and a literature review Dermatol Ther 28 5 2015 287 290 25845419 10.1111/dth.12233

Klein KL Pittelkow MR. Tissue plasminogen activator for treatment of livedoid vasculitis Mayo Clin Proc 67 1992 923 933 1434852 10.1016/s0025-6196(12)60922-7

Kofler K Strölin A Geiger V Kofler L. Intravenous immunoglobulin therapy in livedoid vasculopathy: Retrospective observation of clinical outcome and patient's activity level J Cutan Med Surg 2021 12034754211003525 10.1177/12034754211003525 PMC8474298 33779349

Kreuter A Gambichler T Breuckmann F Bechara FG Rotterdam S Stücker M Pulsed intravenous immunoglobulin therapy in livedoid vasculitis: An open trial evaluating 9 consecutive patients J Am Acad Dermatol 51 2004 574 579 15389193 10.1016/j.jaad.2004.05.003

Krueger S McLean R Amano S Belazarian L Primary livedoid vasculopathy associated with mononeuritis multiplex Dermatol Online J 26 7 2020 13030/qt4c80g04v 32898400

Kunzler E Chong BF. Ulcerative livedoid vasculopathy responding to clopidogrel JAAD Case Rep 4 2 2018 203 205 29892667 10.1016/j.jdcr.2017.09.003 PMC5993557

Lee JH Choi HJ Kim SM Hann SK Park YK. Livedoid vasculitis responding to PUVA therapy Int J Dermatol 40 2001 153 157 11328402 10.1046/j.1365-4362.2001.01183.x

Lee SS Ang P Tan SH. Clinical profile and treatment outcome of livedoid vasculitis: A case series Ann Acad Med Singap 32 6 2003 835 839 14716957

Lee JM Kim IH. Case series of recalcitrant livedoid vasculopathy treated with rivaroxaban Clin Exp Dermatol 41 5 2016 559 561 26993107 10.1111/ced.12829

Lee JS Cho S. Livedoid vasculopathy in Koreans: Clinical features and response to rivaroxaban treatment J Eur Acad Dermatol Venereol 34 2020 e176 e178 31793049 10.1111/jdv.16129

Leisenring NH Rogers JL Telloni S Mansoori P Al-Rohil RN Marano AL. Successful treatment of painful cutaneous vasculopathy with rivaroxaban in a patient with systemic lupus erythematosus J Drugs Dermatol 19 5 2020 544 546 32484618

Llamas-Velasco M Muñoz-Hernández P Lázaro-González J Reolid-Pérez A Abad-Santamaría B Fraga J Thrombotic occlusive vasculopathy in a skin biopsy from a livedoid lesion of a patient with COVID-19 Br J Dermatol 183 3 2020 591 593 32407552 10.1111/bjd.19222 PMC7272899

Magy N Algros MP Racadot E Gil H Kantelip B Dupond JL. Livedoid vasculopathy with combined thrombophilia: Efficacy of iloprost Rev Méd Interne 23 6 2002 554 557 12108180 10.1016/s0248-8663(02)00611-2

Marzano AV Vanotti M Alessi E. Widespread livedoid vasculopathy Acta Derm Venereol 83 6 2003 457 460 14690343 10.1080/00015550310015455

McCalmont CS McCalmont TH Jorizzo JL White WL Leshin B Rothberger H. Livedo vasculitis: Vasculitis or thrombotic vasculopathy? Clin Exp Dermatol 17 1992 4 8 1424259 10.1111/j.1365-2230.1992.tb02522.x

Meiss F Marsch WC Fischer M. Livedoid vasculopathy. The role of hyperhomocysteinemia and its simple therapeutic consequences Eur J Dermatol 16 2 2006 159 162 16581568

Mendiratta V Malik M Yadav P Nangia A. Cilostazol: A novel agent in recalcitrant livedoid vasculopathy Indian J Dermatol Venereol Leprol 82 2 2016 222 224 26345653 10.4103/0378-6323.164217

Micieli R Alavi A. Treatment for livedoid vasculopathy: A systematic review JAMA Dermatol 154 2 2018 193 202 29141075 10.1001/jamadermatol.2017.4374

Miguel D Elsner P Goetze S. Chronic leg ulcerations associated with livedoid vasculopathy successfully treated with rivaroxaban Clin Exp Dermatol 45 1 2020 120 122 30767258 10.1111/ced.13943

Milian G. Les atrophies cutanees syphilitiques Bull Soc Fr Dermatol Syph 36 1929 865 871

Mofarrah R Aberer W Aberer E. Treatment of livedoid vasculopathy with alprostadil (PGE-1): Case report and review of published literature J Eur Acad Dermatol Venereol 27 2 2013 e252 e254 22364635 10.1111/j.1468-3083.2012.04480.x

Monshi B Posch C Vujic I Sesti A Sobotka S Rappersberger K. Efficacy of intravenous immunoglobulins in livedoid vasculopathy: Long-term follow-up of 11 patients J Am Acad Dermatol 71 4 2014 738 744 25022849 10.1016/j.jaad.2014.05.039

Murrell DF Jensen J O'Keefe EJ Failure of livedoid vasculitis to respond to tissue plasminogen activator Arch Dermatol 131 2 1995 231 232 7857130

Nakamura S Kishibe M Nishi K Hashimoto Y Takeda K Mizumoto T Livedoid vasculopathy; favorable clinical response with low dose warfarin Eur J Dermatol 21 6 2011 1011 1012 21914587 10.1684/ejd.2011.1529

Nakayama T Mizutani K Hanamura I Kato H Takami A Takeshita K Livedoid vasculopathy and popliteal artery occlusion in a patient with protein S deficiency J Dermatol 44 2 2017 198 201 27774697 10.1111/1346-8138.13652

Noda S Asano Y Yamazaki M Ichimura Y Tamaki Z Takekoshi T Severe livedoid vasculopathy associated with antiphosphatidylserine-prothrombin complex antibody successfully treated with warfarin Arch Dermatol 147 5 2011 621 623 21576587 10.1001/archdermatol.2011.106

Nuttawong S Chularojanamontri L Trakanwittayarak S Pinkaew S Chanchaemsri N Rujitharanawong C. Direct immunofluorescence findings in livedoid vasculopathy: A 10-year study and literature review Clin Exp Dermatol 46 3 2021 525 531 32986882 10.1111/ced.14464

Okada E Nagai Y Ishikawa O. A case of widespread livedoid vasculopathy with pain but no systemic symptoms Acta Derm Venereol 88 3 2008 298 299 18480943 10.2340/00015555-0413

Oravec S Ronda N Carayon A Milliez J Kazatchkine MD Hornych A. Normal human polyspecific immunoglobulin G (intravenous immunoglobulin) modulates endothelial cell function in vitro Nephrol Dial Transplant 10 1995 796 800 7566606

Osada SI Kimura Y Kawana S. Case of livedoid vasculopathy with peripheral neuropathy successfully treated with low-dose warfarin J Dermatol 37 1 2010 98 101 20175830 10.1111/j.1346-8138.2009.00754.x

Ozden MG Ozdemir H Şenturk N. Intravenous immunoglobulin in resistant livedoid vasculopathy: Analysis of a case series Dermatol Ther 33 2 2020 e13229 31965687 10.1111/dth.13229

Pitarch G Rodríguez-Serna M Torrijos A Oliver V Fortea JM. Treatment of livedoid vasculopathy with short-cycle intravenous immunoglobulins Acta Derm Venereol 85 4 2005 374 375 16191872 10.1080/00015550510027865

Purcell SM Hayes TJ. Nifedipine treatment of idiopathic atrophie blanche J Am Acad Dermatol 14 5 1986 851 854 Pt 1 3711393 10.1016/s0190-9622(86)80551-5

Ravat FE Evans AV Russell-Jones R Response of livedoid vasculitis to intravenous immunoglobulin Br J Dermatol 147 2002 166 169 12100203 10.1046/j.1365-2133.2002.04755.x

Ray R Sharma A Vasudevan B Sridhar J Deo R Mohanty CS. Livedoid vasculopathy with hyperhomocysteinemia responding to hyperbaric oxygen therapy Indian J Dermatol 60 5 2015 524 10.4103/0019-5154.159657 PMC4601462 26538741

Rizzo SC Grignani G Gamba G Nalli G. Fibrinolysis induced by danazol Blut 53 1986 351 352 3756360 10.1007/BF00320896

Rujitharanawong C Chularojanamontri L Trakanwittayarak S Pinkaew S Nuttawong S. Livedoid vasculopathy: Clinical course and long-term outcome in Asian patients with a review of the literature Dermatol Ther 34 1 2021 e14569 33219608 10.1111/dth.14569

Rustin MH Bunker CB Dowd PM. Chronic leg ulceration with livedoid vasculitis, and response to oral ketanserin Br J Dermatol 120 1989 101 105 2638912 10.1111/j.1365-2133.1989.tb07771.x

Sams WM Jr Livedo vasculitis. Therapy with pentoxifylline Arch Dermatol 124 5 1988 684 687 3364993

Sankar A Hinshaw K. Livedoid vasculopathy and pregnancy Int J Gynaecol Obstet 107 3 2009 248 249 19647821 10.1016/j.ijgo.2009.06.020

Saoji V Madke B. Use of low-dose oral warfarin in three cases of livedoid vasculopathy Indian J Dermatol 62 5 2017 508 511 28979014 10.4103/ijd.IJD_564_16 PMC5618839

Schroeter AL Copeman PW Jordon RE Sams WM Jr Winkelmann RK. Immunofluorescence of cutaneous vasculitis associated with systemic disease Arch Dermatol 104 1971 254 259 4398554

Schroeter AL Diaz-Perez JL Winkelmann RK Jordan RE. Livedo vasculitis (the vasculitis of atrophie blanche). Immunohistopathologic study Arch Dermatol 111 1975 188 193 1090260

Shen X Yu RX Shen CB Li CX Jing Y Zheng YJ Dermoscopy in China: Current status and future prospective Chin Med J 132 2019 2096 2104 31433330 10.1097/CM9.0000000000000396 PMC6793796

Song CH Shin DS Jang JW Kim TL Kim YG Kim JS A case of livedoid vasculopathy successfully treated with sulodexide Ann Dermatol 32 6 2020 508 511 33911794 10.5021/ad.2020.32.6.508 PMC7875231

Tsutsui K Shirasaki F Takata M Takehara K. Successful treatment of livedo vasculitis with beraprost sodium: A possible mechanism of thrombomodulin upregulation Dermatology 192 2 1996 120 124 8829492 10.1159/000246335

Tubone MQ Escobar GF Peruzzo J Schestatsky P Maldonado G. Livedoid vasculopathy associated with peripheral neuropathy: A report of two cases An Bras Dermatol 88 6 2013 227 229 Suppl 1 24346927 10.1590/abd1806-4841.20132363 PMC3876016

Tuchinda P Tammaro A Gaspari AA. Successful long-term use of intravenous immunoglobulin to treat livedoid vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity Arch Dermatol 147 10 2011 1224 1225 22006147 10.1001/archdermatol.2011.274

Tuchinda C Leenutaphong V Sudtim S Lim HW. Refractory livedoid vasculitis responding to PUVA: A report of four cases Photodermatol Photoimmunol Photomed 21 2005 154 156 15888134 10.1111/j.1600-0781.2005.00151.x

Valentim FO Tsutsui GM Miot HA. Recrudescence of livedoid vasculopathy induced by COVID-19 Int J Dermatol 60 5 2021 e185 e187 33527356 10.1111/ijd.15423 PMC8013770

Vasudevan B Neema S Verma R. Livedoid vasculopathy: A review of pathogenesis and principles of management Indian J Dermatol Venereol Leprol 82 2016 478 488 27297279 10.4103/0378-6323.183635

Verma V. Livedoid vasculopathy managed with hyperbaric oxygen therapy Med J Armed Forces India 69 2 2013 202 203 10.1016/j.mjafi.2013.02.009 PMC3862796 24600105

Vieira R Bernardes JM Pinto JA Costa L. Livedoid vasculopathy–A challenging disease Acta Reumatol Port 41 3 2016 273 274 27155327

Yang CH Ho HC Chan YS Liou LB Hong HS Yang LC. Intractable livedoid vasculopathy successfully treated with hyperbaric oxygen Br J Dermatol 149 2003 647 652 14511004 10.1046/j.1365-2133.2003.05546.x

Yang CH Shen SC Hui RC Huang YH Chu PH Ho WJ. Association between peripheral vascular endothelial dysfunction and livedoid vasculopathy J Am Acad Dermatol 67 1 2012 107 112 21982058 10.1016/j.jaad.2011.07.021

Yong AA Tan AW Giam YC Tang MB. Livedoid vasculopathy and its association with factor V Leiden mutation Singapore Med J 53 12 2012 e258 e260 23268168

Yoshioka K Tateishi C Kato H Chen KR. Systemic lupus erythematosus with refractory ulcerated livedoid vasculopathy: Successful treatment with intravenous immunoglobulin and warfarin Clin Case Rep 6 11 2018 2045 2047 30455888 10.1002/ccr3.1803 PMC6230605

Wakelin SH Ellis JP Black MM. Livedoid vasculitis with anticardiolipin antibodies: Improvement with danazol Br J Dermatol 139 1998 935 937 9892980 10.1046/j.1365-2133.1998.02541.x

Weishaupt C Strölin A Kahle B Kreuter A Schneider SW Gerss J Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): A multicentre, single-arm, open-label, phase 2a, proof-of-concept trial Lancet Haematol 3 2 2016 e72 e79 26853646 10.1016/S2352-3026(15)00251-3

Weishaupt C Strölin A Kahle B Kreuter A Schneider SW Gerss J Characteristics, risk factors and treatment reality in livedoid vasculopathy–A multicentre analysis J Eur Acad Dermatol Venereol 33 9 2019 1784 1791 31009111 10.1111/jdv.15639

Wen J Li XH Yang QP Yu JB. Clinical and dermoscopic features of livedoid vasculopathy Chin Med J (Engl) 33 17 2020 2137 2138 10.1097/CM9.0000000000001048 PMC7478387 32804736

Winchester DS Drage LA Davis MD. Response of livedoid vasculopathy to rivaroxaban Br J Dermatol 172 4 2015 1148 1150 25255997 10.1111/bjd.13428

Winkelmann RK Schroeter AL Kierland RR Ryan TM. Clinical studies of livedoid vasculitis (segmental hyalinizing vasculitis) Mayo Clin Proc 49 1974 746 750 4153802

Zeni P Finger E Scheinberg MA. Successful use of rituximab in a patient with recalcitrant livedoid vasculopathy Ann Rheum Dis 67 2008 1055 1056 18556452 10.1136/ard.2007.083931